Ординатура / Офтальмология / Английские материалы / Training‐induced Visual Field Recovery in Chronic Stroke Patients_Bergsma_2011

VFE that is found with standard or customised perimetry does not necessarily correspond to a normal visual performance. Whereas with a healthy, unaffected visual field complex reverse stimuli can be perceived, this does not automatically hold true for recovered visual fields (Sabel, 2006). Possibly, recovered field areas can be used to perceive near or super threshold stimuli only. Of course, when a visual field area is transformed from a blind to a partially functional field by training, the patient may nevertheless gain considerably. For example, if a former blind field can be used to detect objects after training, the objects can be avoided without actually recognizing what it is. In other words, those patients that only recover in terms of detection can still be considered visually rehabilitated with RFT (Caplan et al., 2005).

4.2.3 New directions. After 2005, the focus of RFT studies shifted from the question whether VFE can be demonstrated in the absence of eye movements to the question whether RFT truly benefits hemianopia patients and whether neural correlates of possible behavioural changes could be found.

For example, Sabel and colleagues studied a large sample (302 patients) and observed moderate to substantial VFE in 70% of the patients, which coincided with the patients that reported subjective improvement. Moreover, avoiding collisions with objects improved in these patients (Mueller, 2007). Kasten et al. studied the stability of VFE two years after training and found that there was no significant decline in the amount of detected stimuli (= steady VFE). They did find, however, that there are patients that need ‘refreshment exercises’ to prevent them from becoming patients with significant decline. On the average, VFE proved to be stable in the follow up study.

In small sample studies, 2 Finnish research groups focused on studying changes in brain activity in order to find correlations with behavioural changes. The group of Laura Julkunen found increased subjective questionnaire scores and enlarged visual fields which could be associated with Visual Evoked Potentials (VEP) (Julkunen, 2003). In a later study, they applied RFT in a single case study and observed VFE in combination with subjective improvement, both of which correlated positively with changes in brain activity as assessed with VEP and with Positron Emission Tomography (PET) (Julkunen, 2006). Both studies thus imply that RFT can induce (small) cerebral reorganisation which is reflected in VFE and in changed brain activity. The group of Lea Hyvärinen used Flicker Training in order to stimulate the blind field. As a result, temporal sensitivity of the VFD increased, which could be demonstrated using VEPs. (Raninen, 2006). In a second study, the same training was presented to a single patient. In this case study, the researchers showed that both the blind field and the intact field were now represented in the intact hemisphere, although training lasted much longer than in other studies (Henriksson, 2006).

Roth et al. went on to use the flicker training described above and compare it to Compensatory Saccade Training (CST). The flicker training was given as control measurement to contrast CST, but it was assumed to be blind field stimulating. The authors stated that their training potentially was restitution training, so they actually wanted to compare RFT and CST. As expected, only CST induced a change in eye movement behaviour (more and faster saccades to the VFD) and no change in VFD itself. The flicker training also did not

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change the VFD, whereas it did in the study of Raninen et al. (Roth, 2009). However, as Julkunen mentioned when citing Kasten et al. (which Roth et al. do not), VFE is only expected to occur after some 50 100 hours of computer assisted training is applied. In the study of Roth et al, Flicker Training (on a PC) took no more than 30 hours.

In recent years, some attempts have been made to introduce new variants of RFT. For example, Kasten et al. studied whether VRT would benefit from co stimulation (training with more than one stimulus), which appeared to make no difference (Kasten et al., 2007). Stimulation deep into the defective field provided for additional detection sensitivity after ‘traditional’ RFT (Hyvärinen 2002; Henriksson 2007; Raninen 2007; Sahraie, 2006; Jobke, 2009). Sabel et al. applied non invasive alternating current stimulation for the treatment of visual field defects in optic neuropathy. The alternating current stimulation induced small, but significant increases of stimulus detection rates in the experimental group but not in the placebo group in visual field examinations and visual acuity. The changes appeared constant at a 2 month follow up (Sabel, 2009).

4.3 Possible mechanisms of recovery.

Our view on how the central nervous system (CNS) responds to injury has undergone large revision in the last decades. Previously, the CNS was considered to be hard wired and unable to respond to injury other than by degeneration although it was recognized that behavioural recovery from brain damage was possible (Finger & Stein, 1982). To date, the neurobiological basis of that recovery is still very unclear but recently, Das & Huxlin (2010) provided for an overview of hypothetical mechanisms that could explain training induced improvements of perception in cases of (partial) cortical blindness. Training could

(1)Stimulate spared islands of cortex within V1,

(2)Induce plasticity in spared perilesional V1,

(3)Reactivate damaged V1,

(4)Strengthen extrastriatal pathways or

(5)Recruit or inhibit visual areas in the intact hemisphere.

In turn, ‘stimulation’, ‘reactivation’, ‘strengthening’ or ‘recruiting’ itself need further theoretical explanation. For example, McMillan et al (1999) report that some degree of neurogenesis is possible in both animals and humans, as shown by Eriksson (1998), who provided post mortem evidence for the neurogenesis of granule cells in the dentate gyrus of the human hippocampus. Other studies used animal models to describe ‘axonal sprouting’ and ‘synaptic regeneration’ in several structures in the CNS and its associated behavioural improvement (e.g. Muller, 1988; Kapfhammer, 1997; Ramirez, 2001; Deller, 2006). An axon or nerve fibre is a long, slender projection of a nerve cell (neuron), which conducts electrical impulses away from the neuron's cell body to its terminals where it connects with dendrites of other neurones by forming synapses. Axonal sprouting is outgrowth of new axon collaterals from surviving neurons (collateral sprouting) which means that connections

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between neurones are strengthened or renewed. These studies describe a single mechanism, although it is probably too naive to assume that a single mechanism could be responsible for recovery from injury. Still, in 1997 Sabel et al. produced an admittedly oversimplified model of postlesion neuroplasticity in the partially injured visual system that was, amongst others, based on the mechanism of axonal collateral sprouting and increased efficiency. The model describes in a crude way how this mechanism of reorganisation can lead to (partial) recovery of vision through adaptation of the surviving neurones (Sabel 1997). Due to the relatively fixed visual topography in the primary visual cortex, field recovery through restitution should be limited when lesions are restricted to the striate cortex. This led to the suggestion that RFT partially resolves a ‘bottleneck’ in the retino geniculo cortical pathway during training so that the undamaged higher cortical areas receive enough information again to perform normally (Kasten, 2000). It is conceivable that such a mechanism also applies to the reciprocal connections between the primary visual cortex and higher visual brain areas.

Another proposed mechanism of reorganisation is the principle of the ‘enlarged receptive fields’. This means that neurones that were responsive to a small visual field area, become responsive to larger visual field areas after a lesion.

‘Axonal sprouting’, ‘synaptic regeneration’ or ‘enlarged receptive fields’ are all small scale, local changes. An example of larger scale reorganization is recruitment of alternative routes or structures (Sahraie, 2007). This means that a brain region takes care of a function that first belonged to another brain region, which was lost due to a lesion. This is for example described by Henriksson et al: they found that after an intensive training, visual information from both hemifields were processed mainly in the intact hemisphere. Thus, a brain area that processed one hemifield only, now processed both hemifields (Henriksson, 2007). A more recent approach to enhance visual functions is the so called ‘blindsight’ paradigm (Stoerig, 2008; Chokron, 2008). Blindsight (or non conscious vision, see §3.1.2: ‘spontaneous adaptation’) can be used for purposes of rehabilitation of visual field defects by stimulating it using forced choice visual tasks in the “blind” field in hemianopia patients. Both this paradigm and the paradigm that was used in the study described in this thesis are based on stimulating a large part of the blind area.

The current models are incomplete and can only partially account for VFE that is observed in several studies. However, they do provide for the important insight that the brain can show plasticity after it has been damaged. Additionally, hypotheses about mechanisms of recovery can provide new grounds for new training strategies (e.g. using moving patterns instead of static stimuli in case research would show a large involvement of V5/MT in VFE)

4.4 Prognostic indicators.

Because visual field recovery is not observed in approximately 30% of all patients and because RFT is quite laborious, the search for prognostic indicators of such a recovery would be the most relevant strategy from a rehabilitative perspective (although not necessarily from a researcher’s perspective). The most likely candidates for significant VFE are patients

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who have incomplete lesions of visual cortex or optic radiation (Zihl & von Cramon, 1985) and who show residual processing of visual stimuli within the VFD, which means that part of the VFD is a relative defect. Standard perimetry can be used to identify relative defects. It must be realized, however, that standard perimetry is a subjective method: the patient must report what is perceived and thus can only report what is perceived consciously. As mentioned in §3.1.2, there appear to be various degrees of awareness of the visual field defect by their ‘owners’ (Zihl, 2000). So, although some residual vision may be present, this may remain unnoticed by the patient during standard perimetry. The full range of residual processing might be made better visible with functional magnetic resonance imaging (fMRI) because this technique does not rely on ‘conscious’ perception, but measures correlates of neuronal mass activity. Thus, patients with a relative defect can be subjected to a fMRI study to evaluate whether visual stimulation in the VFD yields significant activations in visual cortex (Miki et al 1996). According to Sabel et al, 10% of residual tissue in a lesioned cortical structure may suffice to enable near normal performance of this structure (rat model; Sabel, 1997). fMRI might serve to identify those patients where this minimal residual structure is still present. Because not everybody is allowed in a MRI scanner (e.g. because someone has metal implants, wears pacemakers, internal electrodes, clips or prostheses or is pregnant) or is otherwise unable to undergo scanning (e.g. in case of claustrophobia), alternative methods to measure brain activity are warranted. Perhaps Visual Evoked Potentials (VEP, an EEG variant), PET or even Magneto encephalography (MEG) measurements could serve as such an alternative non invasive technique. However, the potential of these non invasive techniques to serve as screening tool for patients has not yet been studied.

5 MOTIVATION FOR THIS STUDY.

After training my first patient in 1995, I was struck by the fact that VFE could be accomplished by repetitively measuring detection thresholds within the VFD. While this could be confirmed in other patients, it also immediately became clear that RFT (the term that I would introduce later to refer to the training), would not be implemented in rehabilitation settings before it had been be piloted by a test implementation in a rehabilitation setting. However, to successfully implement a rehabilitation method in a rehabilitation setting, there must be good reasons to do so. Therefore the following main research questions were raised to scrutinize the training method ‘in the lab’:

1.What are the characteristics of VFE after training/how useful is the regained visual field area? (Chapter 2)

2.How does VFE develop during training and is VFE development ‘contaminated’ by eye movements? (Chapter 3)

3.Can we determine any transfer effects from visual detection to other visual functions or visually guided motor tasks? (Chapter 4, 5)

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4.Can we identify a psychophysical indicator for significant performance gain? (Chapter 4, 5)

5.Can we identify a cortical indicator for significant performance gain? (Chapter 6)

6 OUTLINE OF THE THESIS.

In this thesis, I describe the experiments that were done in order to assess whether treatment of hemianopia by RFT can lead to visual field recovery in patients with acquired brain damage and, if it does, to what degree.

Chapter 1 introduces the concept of visual field defects, its origins, its consequences and its possibilities of recovery, both natural and training induced.

Chapter 2 describes the experiment that was carried out to define the properties of the regained visual field after RFT. The aim of RFT is visual field enlargement, but the next important question is: can the VFE be used for other visual functions than mere processing of the trained white stimulus? In other words: what is the quality of the visual field area that was regained after training in terms of elementary visual functions? Spatial properties of the regained visual field area were tested by measuring peripheral acuity (instead of central acuity, which is what is generally known as ‘acuity’). Temporal properties were tested using a CFF paradigm: a stimulus is flickered on and off with increasing frequency. The dependent variable is the frequency at which the flickering stimulus merges into one stable stimulus. As a third property, colour perception was measured. Spatial and temporal properties were compared to measurements in control subjects and on corresponding locations in the contralateral unaffected fields; colour perception was compared only to perception on corresponding locations in the contralateral unaffected visual field. It was observed that after training, all these three measures showed values that are comparable to normal values, indicating that the regained visual field area is actually used for processing visual information and that VFE is not restricted to the stimulus that was used for training.

Chapter 3 describes how VFE develops during training. To be able to observe a day to day development of stimulus detection, patients were trained personally (as opposed to PC training at home) on a daily basis. We found that during training, the visual field enlarges gradually. Apparently, the visual field area that is potentially sensitive for recovery does not recover homogeneously. Areas that are close to the border between the healthy and the affected healthy visual field recover first. In a later phase of training, a more peripherally located area recovers. Still later, an even more peripherally located area recovers and so on. This is somewhat to be expected when one realizes that the area between the healthy and the blind visual field usually is an area of residual function which shows a gradient. So, next to the healthy field, visual function is slightly reduced, whereas next to the blind area it is profoundly reduced. This has important therapeutic implications: training can be directed to the border area alone and stimulus locations can ‘travel along’ with the shifting border

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during training. This enables the patient to give many positive responses which will serve motivation to keep up with the training regime.

Chapter 4 describes an experiment in which we studied how colour and shape perception and reading speed change as a result of training. In a group of 12 patients, reading speed was measured. 9 patients showed VFE of whom 7 showed a significant increase in reading speed. From this group of 12 patients, we studied colour and shape stimuli discrimination in 7 patients. 6 patients showed VFE of whom 3 patients showed a significant increase in the proportion correctly discriminated colour and shape stimuli. The proportion of patients that show VFE concurs with results from other studies: about 75% of the patients show VFE after training. However, VFE does apparently not always lead to (significant) behavioural change. To establish when a VFE leads to improvement, a measure was developed that expresses VFE as estimated cortical surface gain (ECSG) in mm, which standardizes the VFE over all eccentricities. Next, VFEs were classified in either of two categories: VFEs resulting in significant performance change and VFEs resulting in non significant performance change or no change at all. The threshold beyond which significant performance change can be expected is an ECSG of about 6 mm cortex. This cortical measure was subsequently compared to the Average Border Shift (ABS) in degrees to assess which of the two best distinguishes patients with and without significant change in performance. It appears that ECSG can better distinguish these groups and is therefore a better description of VFE than ABS.

Chapter 5 is a description of the link between VFE and behavioural measures, instead of elementary functions. We studied how oculomotor behaviour in a driving simulator is modulated by visual training of hemianopia patients. It appeared that some patients increase saccades towards their HVFDs in the driving simulator. We again converted VFE into ECSG and observed that the 2 patients with the largest VFEs also showed significantly changed oculomotor behaviour, which –at a trend level also improved driving performance in the simulator after training. In this experiment, the threshold VFE appeared to be about 10 mm cortex. However, the conversion to ECSG was initially based on the central, horizontal VFE only. In chapter 7 (Discussion), the conversion of VFE to ECSG for the 6 patients in the car driving study is recalculated according to the calculation described in chapter 4 (thus, for the whole trained field). When this was done, the threshold was found to be somewhere between 4 and 7 mm, which fits the calculation in chapter 4, that puts the threshold VFE at about 6 mm.

In Chapter 6 an fMRI experiment is described. It was our first attempt with a small group of patients (n=8) to find out whether training effect can be made visible in the brain. At the same time we wanted to find out whether an fMRI Retinotopic Mapping procedure in conjunction with traditional, subjective perimetry could serve as a predictor for expected training effect. Predicting VFE would be based on the assumption that presence of brain activations (objective fMRI perimetry) related to a visual field area of which the patient reports to be ‘blind’ (subjective Goldmann perimetry) represents potential for training. We find some significant changes in activation of some voxels in V1, V2 and V3. These are,

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however, not enough to account for the found perimetric VFEs.

Although we have found changes in receptive field locations and sizes that could return vision to a small portion of the visual field in patients with cerebral blindness, we found no evidence for extensive representation of the regained visual field before or after training. So, we did not observe changes in early visual field maps that could account for large increases in visual field that were observed in some patients, which means that we could not prove the existence of residual capacity in early visual field maps.

In Chapter 7 all results of the previous chapters are discussed (General Discussion) and some speculations are given concerning how RFT leads to VFE. Also, a brief outlook on future research is presented.

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Chapter 2

Properties of the Regained Visual Field after Visual Detection Training of Hemianopsia Patients

D.P. Bergsma and G.J. van der Wildt

Published in: Restorative Neurology and Neuroscience, 2008, 26: 365 – 375.

Abstract.

Purpose: to study the quality of the visual field areas that were regained after training. In those areas, we measured some of the elementary visual properties that make up the quality of visual functioning in daily life. This was to provide information about whether the functional visual field had been enlarged.

Methods: Patients with visual field defects after a CVA were trained to detect stimuli presented in the border area of the visual field defect. Then, in the regained areas, we measured visual acuity as a measure for spatial properties. Secondly, to assess for temporal properties we measured critical flicker frequency (CFF). Finally, we studied colour vision as a third property of the regained areas.

Results: since we could not predict where restoration of visual fields would occur, it was unclear where to perform the pre training measurements and, consequently, we did not present pre post comparisons. However, despite the fact that training was carried out with the use of stationary simple white light stimuli, we could assess acuity, CFF and colour vision in the regained areas. The performance of the patients during testing of the elementary properties appeared to be almost normal when compared to control subjects and comparable to the patient’s own ipsilesional visual field.

Conclusions: These results support the idea that the regained visual fields that emerged after training can actually be used for other visual functions than processing the stimuli that were used during training.

Keywords: Cerebral blindness, visual quality, visual training, rehabilitation, recovery

Introduction

Cerebral blindness is a condition in which a person suffers from visual field defects due to damage in the brain. Often, the consequence is a homonymous hemianopsia in which half the visual field is affected in both eyes. In the last decade, visual restoration training has been proposed as a method for VFE and a substantial number of studies show that this training can lead to enlargement of the responsive visual field (e.g. Julkunen, 2003; Kasten, 1995; 1998 a,b, 1999, 2000, 2001, 2006; Poggel, 2001, 2004, 2006; Sabel, 2000, 2005; Werth, 1999; Zihl, 1979 1990). In our own studies, we also found that visual detection training resulted in partial recovery of affected visual fields (Van der Wildt, 1998; Bergsma, 2000). However, these findings could not be confirmed in some other studies: VFEs after visual restoration training were not found (Reinhard, 2005) in these studies and the virtues of the training are therefore still not uniformly accepted (Horton 2005 a,b; Plant 2005). Saccadic eye movement training has also been applied as a method for expanding the visual field (Nelles, 2001; Zihl, 1981, 1986, 1995, 2006) and again, some researchers did not observe VFE (Zihl 1986, 1995).

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For implementation of visual training in a rehabilitation clinic, it is important to know what the visual properties are of the visual field parts that have been regained after visual detection training. This quality is relevant for defining the usefulness of these regained visual fields in daily life situations and thus the degree of visual rehabilitation after training. For example, in addition to describing field enlargements after training, researchers have also studied transfer of vision restoration training effects to colour and form perception. In particular, Kasten and co workers described this transfer to form and colour perception in detail (Kasten, 1998, 1999, 2000; Poggel, 2001). Pothoff (1995) described how training with specific stimuli (colour, white light and gratings) leads to field enlargements for those specific stimuli. The goal of the present study was to obtain evidence of the possible usefulness of a regained visual field area after training. We therefore studied three elementary visual functions in the regained areas of three trained patients. These were: (1) visual acuity, as a measure of spatial resolution of the visual system, (2) critical flicker fusion, as a measure of temporal resolution of the visual system and (3) colour identification. The regained area was defined using a Goldmann perimeter.

Methods

Subjects

Experimental subjects (patients) were all volunteers that were screened only to the degree that they had a visual field defect as a consequence of their brain damage and that they did not have other, confounding disabilities that rendered training impossible, such as sensory aphasia or visuo spatial neglect (assessed with the Line bisection task). Also, colour vision should be unaffected in healthy visual fields, which was confirmed by the fact that the 4 test colours could be correctly identified both in the ipsilesional field and the spared areas of the contralesional field. Control subjects were six healthy individuals: 4 males and 2 females (table 2.1). Control subjects are denoted as C1 to C6.

Training

Training was carried out monocularly, because we wanted to be able to monitor fixation visually. To do so, the eye under examination had to be placed centrally in the perimeter so that it is visible to the experimenter. We also needed to train monocularly to enable blind spot mapping, which could serve as a calibration of central eye fixation. A training session took 30 minutes for each eye. Patients were trained by repeated trials of detection threshold measurements in the affected parts of the visual field. For presentation of stimuli a manually operated Goldmann perimeter was used, so that the stimuli could be presented very precisely on fixed retinal locations. Training on a Goldmann perimeter also provided for continuous monitoring of patient reports about visual perception of stimuli during all training sessions. Finally, the Goldmann perimeter is considered a standard in detecting visual field defects in cases of hemianopsia, glaucoma and macula degeneration (Mills, 2007; Riemann, 2000; Smith, 1987; Stewart, 1995; Wong, 2000). The stimulus, presented against a white background, was a white, circular shaped patch (Goldmann stimulus size IV: Ø=1°). The

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